The qualitative and quantitative acquisition of morphological, functional and biochemical parameters using imaging methods is the basis for a plurality of medical research and application areas. An overview over known imaging methods is given in “Scaling down imaging: Molecular mapping of cancer in mice”, R. Weissleder, Nat Rev Cancer (1/2002), Volume 2, 1-8. Two known imaging methods, which are applied e. g. in tumor research, are positron emission tomography (PET) and optical imaging techniques.
PET is a radiotracer imaging technique in which positron-emitting nucleids are administered into the imaged object. The positrons annihilate with surrounding electrons in the imaged object to produce a pair of gamma-rays, each having 511 keV of photon energy, travelling in nearly opposite directions. These gamma-rays are detected by a PET scanner which allows the determination of the location and direction in space of the trajectories of the gamma-rays. Tomographic reconstruction methods are then used to reconstruct a PET image from numerous determined trajectory lines. PET is a clinical imaging modality for non-invasive assays of biochemical processes. The imaging procedure can be repeatedly performed, thereby allowing each patient/animal to be used as its own control. Positron-labelled compounds have been synthesized for a variety of molecular targets, with examples of biological processes ranging from receptors and synthesis of transmitters in cell communication, to metabolic processes and gene expression. Subsequent transversal views of reconstructed projection or sinogram data of the imaged object developed by this technique are used to evaluate a variety of diseases. Clinical key objectives of PET in oncology are to determine and grade tumor mass, to establish whether a tumor is benign or malignant, to locate the site of primary disease, to detect metastatic disease, to identify multi-focal lesions, to determine the extent of tumors for treatment planning, to direct biopsy, to verify prognosis, to monitor response to treatment, to detect local or distant recurrence and to assess residual mass. In animal research, PET has been used extensively in the past for studies of non-human primates and other animals. Different PET-scanner designs for the imaging of small animals are described in “Molecular imaging of small animals with dedicated PET tomographs”, A. F. Chatziioamiou, Eur J Nucl Med (2002) 29: 98-114.
Further imaging methods for in-vivo examination known in the state-of-the-art are optical imaging techniques including fluorescence or bioluminescence imaging. In fluorescence imaging, light of one excitation wavelength illuminates the imaged object, resulting in a shifted emission wavelength, that can be collected by CCD-cameras. The imaged object is labelled for this purpose using a variety of fluorescence probes. Smart probes have been developed, that can be activated and detected only when they interact with a certain target, e. g. a small molecule, peptide, enzyme substrate or antibody. Bioluminescence imaging is used to optically detect photons, that are emitted from cells, that have been genetically engineered to express luciferases, catalysts in a light generating reaction, through the oxidation of an enzyme-specific substrate (luciferin). Unlike fluorescence approaches, the imaged object does not need to be exposed to the light of an external light source, the technique being based upon the internal light produced by the luciferases.
Optical planar imaging and optical tomography (OT) are emerging as alternative molecular imaging modalities, that detect light propagated through tissue at single or multiple projections. A number of optical-based imaging techniques are available, from macroscopic fluorescence reflectance imaging to fluorescence imaging/tomography, that has recently demonstrated to localize and quantify fluorescent probes in deep tissues at high sensitivities at millimeter resolutions. In the near future, optical tomography techniques are expected to improve considerably in spatial resolution by employing higher-density measurements and advanced photon technologies, e. g. based upon modulated intensity light or very short photon pulses. Clinical optical imaging applications will require high efficient photon collection systems. While PET is a standard method in cancer diagnostics in humans for almost a decade now, OT has recently also found applications, such as imaging of breast cancer, brain function and gene expression in vivo. Primary interest for using optical imaging techniques lies in the non-invasive and non-hazardous nature of optical photons used, and most significantly in the availability of activateable probes that produce a signal only when they interact with their targets—as compared to radiolabelled probes which produce a signal continuously, independent of interacting with their targets, through the decay of the radioisotope. In OT, images are influenced greatly by the spatially dependent absorption and scattering properties of tissue. Boundery measurements from one or several sources and detectors are used to recover the unknown parameters from a transport model described, for instance, by a partial differential equation. The contrast between the properties of diseased and healthy tissue can be used in clinical diagnosis.
In the state of the art PET imaging and optical imaging are two imaging techniques, which are applied separately, using two separate devices successively. A single reporter gene, which is dual-labelled for PET and optical imaging, is described in “Optical bioluminouscence and positron emission tomography imaging of a novel fusion reporter gene in tumor xenografts of living mice” P. Ray et al., Cancer Research 63, 1160-1165, Mar. 15, 2003. Therein, a single substrate is dual-labelled and thus can be imaged by the two different imaging modalities. The imaged mice were therefor first scanned using a cooled CCD camera (optical imaging) followed by a separate micro PET scan.
Another paper describing a combination of the two techniques is “In-vivo molecular-genetic imaging: multi-modality nuclear and optical combinations”, R. G. Blasberg, Nuclear Medicine and Biology 30 (2003) 879-888. By using multi-modality reporter constructs (coupled nuclear and optical reporter genes), which incorporate the opportunity for simultaneous PET, fluorescence and/or bioluminescence imaging, many of the shortcomings of each modality alone can be overcome. Until the presence, two separate imaging systems are used successively to acquire the imaging data of an imaged object with such multi-modality reporters.
A comparison of the images obtained by the two imaging methods is possible only to a limited extent since they cannot be obtained simultaneously. The problems of excessive and prolonged burdening of the subject to be examined, the non-reproducibility of kinetic studies, the non-identical imaging geometries, animal and organ movement and the correct superposition of the images arise, when the two methods are carried out successively.
In D. Prout et. al: <<Detector Concept for OPET, a Combined PET and Optical Imaging System>>, 2003 IEEE Nuclear Science Symposium Conference Record, vol. 5 (2003-10-19), pages 2252-2256, ISBN: 0-7803-8257-9 an imaging system is presented, which is described as being capable of detecting and simultaneously imaging both PET and optical signals generated by bioluminescence probes, only. In this imaging system modified PET detectors are used for both, γ-ray detection and optical imaging. As a precondition for the optical imaging the surface of the imaged object needs to be in contact with the crystals of the PET detector in order to define a field-of-view for optical photons. This condition, however, cannot be achieved for complex geometrical objects such as mice, so that the proposed device produces optical projections of low quality. The presented imaging system is not capable of fluorescence imaging and is classified as a measurement device, which has to be in contact with the measured object. The device described by Prout et. al. used for optical imaging does not incorporate a laser or other light source. This is the reason why this device has only been used for bioluminescence imaging, not however for fluorescence imaging which requires an external light source. Furthermore a PET detector is not designed as an optical imaging detector and is not sufficiently sensitive to light photons.